This invention relates generally to enhance medical imaging. More particularly, the present invention relates to metal particle agents and the methods of their use in medical imaging.
The practice of medicine was revolutionized by the discovery of x-rays by Roentgen in 1895. Today, over 300 million diagnostic x-ray examinations are performed each year in the United States. Even with the rapid growth of Magnetic Resonance Imaging (MRI), 75 to 80% of all diagnostic imaging utilize X-rays.
X-rays show bone structure well, but for better delineation of soft tissue structures, including vasculature, the alimentary canal (digestive tract), and bladder, contrast agents are required to enhance image contrast. Sodium iodide was first used in 1923 to opacify the bladder, and shortly afterwards the intravenously administered agent sodium 5-iodo-2-pyridone-N-acetate (Uroselectan) was introduced for imaging the urinary tract. Water soluble, ionic, triiodobenzene contrast agents were then developed for intra vascular use, such as diatrizoate and ioxaglate. These, however, unpredictably and occasionally caused moderate to severe anaphylactic, cardiovascular and pain reactions. Part of this toxicity was later found to be a result of the high osmolality, so agents that were non-ionic with lower osmolality were developed, such as the monomeric iohexol (also called by the trade names Omnipaque and Exypaque), based on German patent 2,726,196, corresponding to U.S. Pat. No. 4,250,113, and a dimeric version with even lower osmolality, iodixanol (trade names Accupaque and Visipaque), described in European patent 108,638.
Currently there are two types of X-ray image contrast enhancing agents approved for human use: a) aromatic iodinated compounds that are water soluble, and b) barium sulfate suspensions, used only for gastrointestinal tract imaging.
The development of the above-mentioned contrasting agents notwithstanding, several serious medical problems persist that affect millions of individuals which could be addressed using even better contrast agents. One such problem is the large number of sudden unexpected heart attacks and deaths that occur. Each year in the U.S. 1,100,000 new and recurrent heart attacks occur, resulting in 500,000 deaths per year. It is the number one killer. Heart attacks often occur suddenly without warning, when a coronary artery with plaque buildup (atherosclerosis) breaks loose, initiating a clot that blocks the artery (myocardial infarction). Heart muscle dies due to lack of oxygen, the heart pumps insufficiently, brain function is destroyed, and the victim commonly may die before adequate treatment is obtained.
Plaque buildup and narrowing of the coronary arteries occurs over a period of years, but few people know the condition of their coronary arteries and the risk and danger thereof. If the condition of the coronary arteries was known, treatments could be administered before the cataclysmic event occurred, and many sudden fatal heart attacks could be avoided. The reason that routine checks of the coronary arteries are not done with annual physicals, or for persons over a certain age or believed to be at risk is that the current best test, coronary angiography, which images the coronary arteries directly and permits visualization of constrictions, is itself an expensive, complicated, time-consuming, and risky procedure. This test involves piercing a leg or arm artery (which is under high pressure) with a needle, snaking a catheter through the arteries to the heart, and watching coronary arterial blood flow in real-time using X-ray fluoroscopy. A very concentrated iodine dye is injected, which, for a few seconds, provides sufficient contrast to allow the coronary arteries to be imaged. This procedure requires the services of a skilled cardiologist and operating team. A number of possibly fatal events could be initiated by the procedure such as blood clots in major, vital arteries (caused by the catheter dislodging pieces of plaque from the artery wall) resulting in stroke, massive reaction to the dye, cardiac arrhythmia, damage or puncture of arteries, infection, hemorrhage, and heart attack.
Coronary angiography carries with it these major complication ratesxe2x80x94death (0.12-0.20%), cerebrovascular accident (0.03-0.20%), myocardial infarction (0.0-0.25%); and minor complication and local infection (0.57-1.6%) or arrhythmia (0.30-0.63%). Total risk of serious complications is 1.7%. About one out of every 600 persons subjected to such trans-arterial coronary angiography die from the procedure alone. Due to the high level of invasiveness and risk, it is not recommended for routine use and especially not for the elderly and those in poor health, namely those who need it most. Yet, about 1,250,000 cardiac catheterizations for coronary angiography are performed annually in the United States at a cost of $5,000 to $6,000 per procedure. The high cost of the procedure and associated risk therefore make routine coronary angiography inappropriate for use as a screening test.
The ability to perform non-invasive coronary angiography would represent a major improvement in patient care. Information regarding coronary anatomy could then be acquired with minimal risk, even for patients in whom coronary angiography is contraindicated due to severe allergic history to current radiographic contrast agents, fever with documented infection, bleeding diatheses, recent gastrointestinal bleeding, or cerebrovascular accident. Follow-up angiographic information in patients undergoing revascularization procedures could also be more readily obtained.
Echocardiography and Doppler techniques use ultrasound, and can be done in a doctor""s office, with no risk. These techniques provide information about the size of the heart chambers, the pumping function, valve function, and blood volume. However, they are not suitable for anatomic evaluation of the coronary arteries Since 1973, Computed Tomography (CT) has grown to become one of the most important radiological examination processes in the industrialized world. CT delineates organs in a new way by producing digitally reconstructed images of cross-sections of a patient. In this way, it achieves a higher than normal sensitivity to improve the natural radiological contrasts between organs. It is exceptionally sensitive to contrast media, moreover, and can detect disease-related abnormalities from the distribution of an intravenous dose of a contrast medium.
Consequently, 60-80% of all CT examinations involve the use of a contrast medium. The primary uses for CT include brain and spine investigations, abdominal and urological studies, and approximately 20% of all CT procedures are performed to investigate the liver. An advanced CT technique, called spiral or helical CT, has been developed which achieves the resolution of normal CT but with shorter examination times and a lower x-ray dose. Multi-slice CT (MSCT) is another improvement, with typically 2 or 4 source/detector pairs operating simultaneously, which can improve the resolution and acquisition time.
Electron Beam Computed Tomography (EBCT), or Ultrafast CT, uses a rapid x-ray scanner, which can freeze the heart beating motion, to visualize calcification in the coronary arteries without use of dyes or catheterization.
Electron Beam Tomography (EBT) scanner is different from conventional (mechanical) CT scanners, focusing an electron beam onto tungsten target rings positioned around the patient. Each sweep of the electron beam produces a continuous 30 degree fan beam of x-rays that pass through the patient to a stationary array of detectors which generates cross-sectional images, with scan times of 50 milliseconds. Exposures can be triggered from an electrocardiogram (ECG or EKG) to visualize a specific part of the beating heart cycle and to reduce overall dose.
Intra vascular ultrasound (IVUS) is an invasive technique, where the sound equipment is on the catheter snaked into the artery. This technique allows the architecture of the wall, its components, size, shape, surface and consistency to be analyzed.
Stress echo combines treadmill exercise with an ultrasound echocardiogram and EKG to measure differences between resting and active states. A low-resolution image is created by moving a transducer over the chest area. This gives some information about heart output and overall function, but is not suitable for anatomic evaluation of the coronary arteries.
In nuclear perfusion studies, single photon emission tomography (SPECT), radioactive isotopes are injected into the patient and detectors yield a low-resolution map of the heart. This test reveals perfusion abnormalities, but does not depict the coronary artery stenosis that cause them nor does it provide direct measurements of coronary artery blood flow. It is not suitable for anatomic evaluation of the coronary arteries.
Positron-emission tomography (PET) utilizes positron emitting radioactive isotopes which are injected into the patient and detectors which yield a low resolution map of the heart. This test also reveals perfusion abnormalities, but due to the limited resolution is not able to show the coronary artery constrictions that cause them nor does it provide direct measurements of coronary artery blood flow. It is not suitable for anatomic evaluation of the coronary arteries.
Some studies have shown sensitivity and specificity for coronary artery disease for Magnetic Resonance Angiography (MRA) to be as high as 80-90%, but others have not found the method to be as accurate. Problems include limited spatial resolution, mis-registration of images acquired over sequential breath holds, and inadequate flow contrast. This last problem might be ameliorated by the use of improved contrast agents. However, resolution is significantly worse than with x-ray angiography, making constrictions more difficult to definitively detect. Further development is required before coronary MRI becomes a standard clinical tool.
Even though each of these alternative technologies has some usefulness in assessing coronary function, all of them fall short of providing the best direct, necessary, and sufficient images needed for life-saving decisions which are possible with contrast-based x-ray angiography. Coronary angiography remains the standard for assessment of anatomic coronary disease, because no other currently available test can accurately define the extent of coronary luminal obstruction. However, because the technique can only provide information about abnormalities that narrow the lumen, it is limited in its ability to accurately define the etiology of the obstruction or detect the presence of non-obstructive atherosclerotic disease. Despite these and other limitations, coronary angiography is the only method currently available for defining the details of the entire coronary endoluminal vascular anatomy, and it provides the reference standard against which other tests are compared. Information derived from such angiograms is the standard by which mechanical interventions and many medical therapies are planned. In addition, prognostic information is also gained from data regarding coronary artery patency.
The Hounsfield Unit (HU) is a measure of the relative density of a structure on Computed Tomography (CT), named after the inventor of CT, Sir Geoffrey Hounsfield. It is used to measure the amount of x-ray attenuation of each voxel in the image; since the voxel is normally represented as a 12-bit number, the scale ranges from xe2x88x921024 to +3071. By definition, water has a HU of zero. Air is xe2x88x921024 HU, fat is xe2x88x9250 to xe2x88x92100, muscle is 40, soft tissue is 30-80, calcification is 80-1000, bone is 800-1000, and metal is 2000. The reading in HU is also called the CT number. The addition of about 42 xcexcg iodine/ml increases the contrast by one HU.
Virtually all possible elements and known compounds have been explored to some extent to find improved x-ray contrast agents. In Metal-Based X-ray Contrast Media, Yu, S. B. and Watson, A. D., Chem.
Rev., vol. 99, pp. 2353-2377, 1999, the authors conclude that xe2x80x9c[f]rom the list of possible heavy metals, we may exclude those metals that are radioactive (Th, U), those that are highly toxic . . . (Hg, Pb, Tl, Cd, Ag) or those that are unduly expensive (Pt, Ir, Os, Au, Pd) from consideration. Furthermore, those elements close to iodine (In-Ba) do not offer any advantages over iodine in terms of their ability to utilize high-energy x-ray photons (thus lowering the radiation exposure to patients) and can also be eliminated. This leaves only the lanthanide metals and Hf, Ta, W, Re, and Bi as potential candidates.xe2x80x9d Unfortunately, no viable candidates have been produced. xe2x80x9cThe challenge to move to an entirely new technology platform and successfully develop an adequate first-generation metal-based compound which could compete with the current generation of iodinated materials is immense and in our minds presently remains unsolved.xe2x80x9d
Briefly stated, the invention in a preferred form is a medical imaging method and contrast agent which contrasts a targeted portion of a body of a living animal. The method includes intravenously administering a quantity of nanoparticles sufficient to contrast the targeted portion of the body under irradiation and irradiating the targeted portion of the body with penetrating radiation. Each of the nanoparticles has a metallic core surrounded by a surface layer including a component having an affinity for the targeted portion of the body.
The targeted portion of the body is irradiated a predetermined period of time after the nanoparticles are administered, such that an optimum combination of targeted portion nanoparticle concentration and targeted portion to background nanopartiacle distribution is achieved.
The metal nanoparticles have a core composed of gold, platinum, palladium, thallium, bismuth, osmium, iridium, silver, tungsten, lead, tantalum, or uranium. The component of the material of the surface layer may be for example, an antibody, an antibody fragment, a peptide, a lipid, a carbohydrate, a nucleic acid, or a drug. The surface layer may also include a component that absorbs X-rays. Either the surface layer or the metallic core may include a radioactive isotope.
In one preferred method, where the targeted portion of the body is cancerous cells, the component of the material of the surface layer is an antibody, an antibody fragment, or a peptide.
In another preferred method, where the targeted portion of the body is a blood clot, the component of the material of the surface layer is anti-fibrin, anti-D-dimer antibodies, or peptides.
If the targeted portion of the body is an atherosclerotic plaque, the component of the material of the surface layer may be either DMP-444 or a lipophilic group.
The location and extent of an infection site may also be determined by extracting blood from the animal, isolating leukocytes or white blood cells from the extracted blood, and labeling the isolated leukocytes or white blood cells with nanoparticles. Nanoparticles of this type are attracted to an infection site.
It is the object of the invention to provide improved medical imaging methods and contrast agents.
It is also an object of the invention to provide medical imaging methods and contrast agents for targeting selective regions of the body.
It is further an object of the invention to provide medical imaging methods and contrast agents for detecting blood vessel abnormalities in the heart, carotid arteries, brain, kidney, extremities, intestine, and other soft tissues.
It is still further an object of the invention to provide medical imaging methods and contrast agents for detecting functional states of tissues.